What are the presentation, diagnosis, complications, and treatment of Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

G6PD Deficiency: Presentation, Diagnosis, Complications, and Treatment

Clinical Presentation

Most individuals with G6PD deficiency remain asymptomatic throughout life until exposed to oxidative triggers. 1

Acute Hemolytic Crisis Symptoms

• Jaundice is the most common presenting sign of acute hemolysis 2
• Anemia with associated fatigue 1
• Back or abdominal pain 1
• Hemoglobinuria (dark urine) 1
• Symptoms typically develop after exposure to oxidative medications, infections, or fava bean ingestion 1, 3

Neonatal Presentation

• Jaundice appearing in the first 24 hours of life 4
• Rapidly rising total serum bilirubin requiring phototherapy or approaching exchange transfusion levels 4
• G6PD deficiency accounts for 31.5% of kernicterus cases in one series, making this a critical diagnosis to identify early 4

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Diagnosis

Quantitative G6PD enzyme activity assay measuring units per gram of hemoglobin (IU/gHb) is the gold standard confirmatory test. 2

When to Screen

• Screen all patients of Mediterranean, African, Indian, or Southeast Asian descent before starting any oxidant drugs 2, 4, 5
• Screen infants with jaundice in the first 24 hours or with rapidly rising bilirubin 4
• Screen before initiating dapsone, primaquine, tafenoquine, or other high-risk medications 4, 5

Critical Timing Considerations for Testing

Avoid testing during or immediately after acute hemolytic episodes, as reticulocytes and young RBCs contain near-normal enzyme levels that will mask the deficiency. 2, 4

• Wait at least 50 days after RBC transfusion before performing enzyme assays, as even 6-12% donor RBC contamination causes false-negative results 4
• Testing 120 days post-transfusion is ideal but often impractical 4
• If testing must occur during acute hemolysis, repeat testing after 3 months for accurate diagnosis 2

Test Selection Based on Patient Population

Qualitative fluorescent spot tests work well for males and homozygous females with severe deficiency (<10% enzyme activity), but quantitative assays or flow cytometry are necessary for heterozygous females. 4

• Qualitative screening is sufficient for initial assessment in most cases 2
• Quantitative testing is required before tafenoquine use—do not use if activity is <70% 4
• Quantitative testing is needed for borderline cases (30-70% activity) to determine specific variant and predict severity 2, 4
• Molecular genetic analysis may be required in heterozygous females when enzymatic testing is inconclusive 4, 1

Laboratory Interpretation

• Calculate percentage of normal activity by dividing patient's G6PD level by laboratory upper limit of normal and multiplying by 100 4
• Elevated indirect bilirubin (>1.0 mg/dL when total bilirubin is ≤5 mg/dL) suggests hemolysis 2
• Consider calculating PK/G6PD ratio or comparing to controls with similar reticulocyte counts for borderline results 4

Sample Handling Requirements

• Whole blood samples remain stable at -20°C and 6°C for up to 14 days, losing only 20% activity over 48 hours 2
• Buffy coat removal or filtration is essential for accurate RBC enzyme measurement—testing whole blood without removing white cells and platelets prevents detection of deficiency 4

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Complications

Acute Hemolytic Anemia

The severity of hemolysis depends on the genetic variant: Mediterranean variant (Gdmed) causes life-threatening hemolysis requiring strict oxidant drug avoidance, while African variant (GdA-) produces milder, self-limited hemolysis. 4, 5

• Mediterranean variant is found predominantly in men from Mediterranean regions, India, and Southeast Asia 5
• African variant (GdA-) is found in 10-15% of Black men and women 5

Neonatal Complications

• Severe hyperbilirubinemia requiring exchange transfusion 4
• Kernicterus in untreated cases 4

Chronic Complications

• Approximately half of G6PD mutations cause chronic nonspherocytic hemolytic anemia in rare patients with sporadic mutations 3

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Treatment

Management of Acute Hemolytic Crisis

Immediately discontinue the offending oxidant medication or trigger. 4

• Monitor for signs of ongoing hemolysis including jaundice 2
• Use ascorbic acid as an alternative treatment for methemoglobinemia in G6PD-deficient patients (do not use methylene blue, which is contraindicated) 4
• Consider exchange transfusion for severe cases of hemolysis 4
• Monitor for rebound methemoglobinemia requiring repeat dosing every 6-8 hours for up to 2-3 days after dapsone exposure 4

Absolutely Contraindicated Medications

Seven medications are definitively contraindicated: Dapsone, Methylthioninium chloride (methylene blue), Primaquine (in severe deficiency), Rasburicase, Pegloticase, and Tafenoquine (if activity <70%). 2, 4, 1

• Aspirin is explicitly contraindicated as it overwhelms the reduced antioxidant capacity 2
• Both primaquine and tafenoquine are contraindicated during pregnancy regardless of G6PD status 5

Medications Requiring Caution or Modified Dosing

Primaquine may be considered in mild to moderate G6PD deficiency (>30% to <70% activity) at reduced dosing of 45 mg once weekly for 8 weeks, but only after G6PD testing and with close hematological monitoring. 4, 5

• Chloroquine/hydroxychloroquine in standard doses appears relatively safe in most G6PD deficient patients 5
• Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely for malaria treatment 5

Safe Alternative Medications

Penicillins, such as amoxicillin, are not contraindicated and can be used in normal therapeutic doses. 2

Common pitfall: While amoxicillin is generally considered safe, one case report documented severe hemolysis after amoxicillin exposure in a G6PD deficient patient 6. Monitor all patients when starting any new medication, even those not traditionally contraindicated.

Alternative Therapies for Specific Conditions

• For dermatologic conditions: use mycophenolate, azathioprine, or methotrexate instead of dapsone 4
• For Pneumocystis prophylaxis: use atovaquone or inhaled pentamidine instead of dapsone 4
• For malaria prophylaxis during pregnancy: chloroquine may be used as it has not been found harmful to the fetus in recommended doses 5

Patient and Family Education

Educate patients and families about when to seek medical attention and screen first-degree relatives of G6PD-deficient patients. 2, 4

• Provide lists of medications and substances to avoid 2
• Emphasize the importance of informing all healthcare providers about G6PD deficiency status 4
• Children of any age can develop hemolysis from contraindicated medications—the same restrictions apply 5